Monday, April 15 2002
All You Need to Know about Breast Cancer and Therapies
Anjali ShaykherAnjali Shaykher is a sophomore majoring in International Politics. The past summer she conducted research at the Cancer Research Center at Jackson Memorial Hospital in Miami, Florida. She studied vitamin-d receptors in prostate cancer and also studied therapy in breast cancer. She does not plan to pursue a career in the medical line, but has spent a great deal of time studying the area.
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Breast Cancer and Ethnic Differences
Breast cancer, the second leading cause of cancer mortality will kill approximately 43,300 women this year in the United States. This malignancy can plague a mother, a sister, a wife or a daughter and thus has wide social and familial implications. Breast cancer results from uncontrolled proliferation of malignant cells resulting in the appearance of a lump or a mass in the breast. The uncontrolled proliferation of breast tumor cells may necessitate surgical removal of either the lump (lumpectomy) or one or both breasts by partial or radical mastectomy. Breast cancer is predominantly a disease of the female sex although in rare cases men can also develop breast tumors. Although women with a family history of breast cancer are at a higher risk of developing tumors, early menarche or late menopause, a first pregnancy past 30 years of age, long-term estrogen therapy, a high fat diet and alcohol use are factors believed to contribute to higher incidence of breast cancer. In addition to family history, race and ethnicity also play a significant role in breast cancer incidence. For example, Caucasian women above the age of 45 have the highest incidence of breast cancer, followed by Native Hawaiians, Afro- Americans, Asians, Hispanics, and Native Americans. Incidence of breast cancer in Afro-Americans under the age of forty-five, surpasses that of the Caucasian women. While Afro-American breast cancer patients have the highest breast cancer mortality rates, the lowest rates are seen in Asians and Alaskan Native patients. Ethnic differences in breast cancer incidence suggest the possible role of life style and diet that may modulate genetic predisposition for the development of breast cancer in different ethnic groups.
Causes and Genetic Basis
The precise biological, genetic, and environmental causes of breast cancer are still being investigated. Recent genetic studies provide strong evidence for a positive correlation between the presence of certain genes and incidence of breast cancer. Through segregation analysis, a method of studying genes that classifies particular traits as having a Mendelian pattern of inheritance, it has been determined that breast cancer is an autosomal dominant inherited predisposition. Studies to find hereditary susceptibility to breast cancer have ultimately led to the discovery of tumor suppressor genes such as BRCA1 and BRCA2. Mutations that alter the function of a gene can result in tumor growth. For example alterations in the BRCA1 gene located on chromosome 17 seems to be associated with 45% of families with breast cancer history. Similarly mutations in a second gene, BRCA2 (located on chromosome 13) also significantly increases the risk of breast cancer.
Although BRCA1 and BRCA2 share very few structural characteristics, their functional similarities provide a strong basis for their influence in breast cancer heritability. The late transcription of both genes in the G1 phase of the cell cycle suggests the role of these genes in DNA synthesis and repair. Furthermore, both genes interact with RAD51, a protein actively involved with repair of double-stranded DNA breaks and homologous chromosome recombination. It is speculated that through their association with RAD51, BRCA1 and BRCA2 are able to interact with each other at DNA synthesis sites after the initiation of DNA damage. Studies with homozygous knockout mice reveal that most mice without BRCA1 or BRCA2 function die in the embryonic stage. Their cells have dysfunctional DNA repair, and BRCA2 deficient cells in particular are hypersensitive to radiation and drugs that cause DNA breaks.
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HER2neu is another important breast cancer related gene located on chromosome 17. This oncogene is a member of the epidermal growth factor family of tyrosine kinases. Her2neu over expression is seen in 20-30% of breast tumor patients. Herceptin, a antibody developed to block Her2neu expression, has been shown to arrest breast tumor growth and is now in clinical use in patients who have over expression of this gene.
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Breast Cancer Therapies
Radiotherapy:
Radiotherapy is based on the use of ionizing radiation to cause DNA damage in tumor cells and thus prevent their proliferation. The two main forms of radiation therapy used for breast cancer are implantation of radioactive seeds in the tumor (brachytherapy), and the use of external beams to irradiate a tumor site. Radiation therapy has proved to be extremely successful in control of early stage breast cancer, and may not require surgical removal of the breasts. Due to DNA damage caused to normal cells in the vicinity of a tumor, radiation may have side effects that usually include skin discoloration and hair loss.
Radiation is often successful alone but may be combined with surgery or chemotherapy for better control of the tumor growth. Recently internal radiation therapy (brachytherapy), which involves insertion of narrow tubes containing radioactive material into the breast tumor, has been introduced. Brachytherapy has proven to be extremely successful in early stage breast cancer patients. It is also cost and time effective, as it allows the radiation to be completed in 1 week instead of 6 weeks, and it minimizes radiation exposure of other normal tissues. It is aesthetically more acceptable as it does not disfigure the breast, and therefore the recovery time is shortened.
Another novel approach for killing breast tumor cells involves the use of extremely low temperatures or cryotherapy. The tumor is frozen by use of liquid nitrogen and then dead tissue is removed. Successful cryosurgery studies have established the proper thermal parameters and cryosurgery is becoming a more useful option for breast cancer treatment.
Surgery:
Surgical intervention, which may involve removal of the tumor lump (lumpectomy) or of the whole breast (mastectomy), has been a standard therapeutic modality for control of this malignancy. If tumor cells are seen in fine needle aspirates (FNA) routinely used for the diagnosis of breast cancer, then lumpectomy is performed. To control more extensive disease, mastectomy, which involves removal of either a portion of the breast or removal of the entire breast along with any lymph nodes that drain the tumor area, is performed. The problem with only removing a certain area of the breast is a greater risk for reoccurrence. Nonetheless, if the cancer is at an early stage, many patients opt for this choice. Side effects and complications which may follow a radical mastectomy can range anywhere from nausea and vomiting to formation of hemaetomas and wound infections.
Hormone Replacement Therapy:
As most of the breast tumor cells depend on the availability of circulating estrogens for their growth, anti-estrogens such as tamoxifen are used in hormone replacement therapy. The additional benefits of hormone replacement therapy are a decreased risk of osteoporosis and cardiovascular disease. However, the disadvantages include increased risk of blood clots, acerbation of preexisting liver disease, increased risk for endometrial cancer, and possibly higher risk of breast cancer. Anti-estrogen hormones such as tamoxifen have been extensively used in management of breast tumors, however, the use of anti-estrogen could increase the relative risk of other cancers such as ovarian or endometrial. Several studies have explored the relationship between hormone replacement therapy and breast cancer and evidence seems to be divided. In one milestone study, the "Nurses Health Study," 121,701 women between the ages of 30 and 55 were monitored for several years. Every two years they answered questionnaires regarding their health status, more specifically their postmenopausal stage, estrogen-progestin usage, and any development of breast cancer. In 1995, The New England Journal of Medicine associated a 46% increased risk of breast cancer with women who had 5 or more years of hormone replacement therapy. Yet not even three weeks later, The Journal of the American Medical Association asserted that combined estrogen-progestin therapy shows no significant increase in breast cancer risk. In view of this controversy, further studies may be needed to determine the benefits and risks of hormone replacement therapy.
The anti-estrogen, tamoxifen has been extensively used and studied for the treatment of breast cancer. Although it acts to block the response of tumor cells to natural estrogens, it behaves like estrogen in other body systems. Thus, the use of tamoxifen may reduce the risk of osteoporosis and heart disease. A National Cancer Institute study on the chemopreventive role of tamoxifen in high at-risk patients, reported 49% reduction in diagnoses of invasive breast cancer in women on tamoxifen. These women also had 50% fewer diagnoses of noninvasive breast tumors. Furthermore, another study indicated that premenopausal women, not just postmenopausal women, and those whose breast cancer had spread to the local lymph glands, benefited substantially from tamoxifen therapy. In spite of these benefits, use of tamoxifen may result in some side effects including, hot flashes, weight gain, vaginal dryness, bleeding, or irritation, irregular periods, dizziness, fatigue, and loss of appetite. Other potential risks of tamoxifen are increased chance of developing cataracts, blood clots, and increased risk of developing uterine cancer.
Hormone Therapy: STAR study:
A recent study (STAR) compared the effects of tamoxifen and raloxifene, another anti-estrogen, in postmenopausal high-risk women. The participants were required to meet certain criteria. They could not have high blood pressure, a history of cancer, strokes, blood clots, or certain types of heart irregularities. Furthermore, any participants who had past hormone therapy were not allowed to participate unless they discontinued the therapy at least 3 months prior to the STAR experiment. Each woman was given 2 pills. One of the pills was either tamoxifen or raloxifene and the other was a placebo; the women did not know which drug they were given. They were required to take these pills every day for 5 years. Oncologists are curious to know about raloxifene as it could be useful in curing breast cancer and has not been shown to increase the risk of endometrial cancer. The major side effects of raloxifene are similar to those of tamoxifen, which include vaginal bleeding and hot flashes. In terms of more serious side effects, women taking raloxifene have three times the chance of developing a pulmonary embolism or deep vein thrombosis. There is limited information on raloxifene since it has only been studied for the past 5 years. The STAR project is still underway and results have yet to be determined.
Estrogen-Progestin Hormone Therapy:
In spite of the fact that estrogen stimulates breast cancer development, hormone therapy combining anti-estrogens with progestins seems to be effective. Progestins are synthetic versions of the hormone progesterone, which is released during the luteal phase of the menstrual cycle. This hormone causes weight gain and during pregnancy is secreted by the ovaries in abundance. In hormone replacement therapy, it does cause a slight weight gain however; it is beneficial because women taking only estrogen increase their risk of endometrial cancer.
Chemotherapy:
Chemotherapy involves drugs that interfere with DNA synthesis or cell division, and is routinely used to control breast tumor growth. Some of the well-known drugs used for treatment of breast cancer include antibiotics (doxorubicin) and alkaloids (taxol). Doxorubicin, one of the best-known breast cancer drugs may cause dose limiting cardiotoxicity, which limits its continued and prolonged use. Some of its other side effects include hair loss, nausea and vomiting, mouth sores or ulcers, reduction in bone marrow function, potential infertility and sensitivity to the sun light.
A new anthracyline antibiotic, epirubicin, was recently introduced for chemotherapy of breast cancer. Although doxorubicin yields good results, its association with high cardiac toxicity can be problematic. A combination with epirubicin has proven to be beneficial in advanced stage breast cancer.
In addition to doxorubicin and epirubicin, taxol, a natural product extracted from the bark of the Pacific Yew and a new semi-synthetic taxane, Taxotere is increasingly used for therapy of advanced stage breast cancer. Taxanes alter the function of microtubules, which are essential for cell division and growth. Side effects of taxanes include, hair loss, numbness in the extremities, diarrhea, nausea, and reduced white blood cell count, which may leave the patient more susceptible to infections. Most of these side effects are temporary and stop when therapy is discontinued.
Relationship between Diet and Cancer
The relationship between consumption of soy products and breast cancer incidence in the Asian population has led to studies seeking to determine if the natural estrogen-like compounds found in soy can prevent breast cancer. These phytoestrogens or plant estrogens, bind to the estrogen receptors of the tumor cells, and thus prevent the natural estrogens from binding to these sites and stimulating tumor initiation or growth. Recent studies by Drs. Daniel Doerge and Daniel Sheehan have suggested that soy does not decrease cancer risk, but in fact increases it. They assert that the isoflavones (phytoestrogens) contain toxins that are hazardous to humans, and furthermore specifically increase the risks for estrogen-triggered breast cancer. In animal studies, soy intake resulted in thyroid disorders and fetal development abnormalities. The soy industry refutes these results by claiming that the soy effects in animals are different than those seen in humans. Nonetheless, further investigation also reveals adverse effects of soy. Soy contains many harmful substances such as phytates, which block the body's uptake of essential minerals like calcium, magnesium, iron and especially zinc. Moreover, soybeans are resistant to long, slow cooking, which is a technique that can reduce phytate concentration. Soybeans have powerful enzyme inhibitors that block the uptake of trypsin and other enzymes that are imperative for protein digestion. These inhibitors that act as "antinutrients" can lead to serious gastric distress, reduced protein digestion, and chronic deficiencies in amino acid uptake. Furthermore, soy products also contain hemagglutinin, a clot promoting substance that causes red blood cells to clump together. These cell clumps prevent the blood cells from absorbing oxygen needed for dispersal through the body's tissues. Despite the fact that fermenting soy deactivates the trypsin and hemagglutin inhibitors, precipitation and cooking do not, and thus, the antinutrients remain a problem. One may ask, what then of the studies performed that reveal the decreased risk of breast cancer in Asian women and their increased intake of soy? However, many of these studies ignored factors such as overall amount of food consumption, physical activities, and basically the many components that play a role in one's lifestyle and diet. In other words, the Asian diet differs from the American diet in more than just soy intake and any of these variables could play a role in the decreased breast cancer rates in Asian women.
Prevention
Breast cancer is a devastating disease and unfortunately, the treatment options are few and have their serious disadvantages. Recent demographic and epidemiological data clearly supports the hypothesis that besides our genetic make up, environmental factors such as exposure to mutagens, pesticides and diet can play a major role in incidence of breast cancer. Thus, controlling these factors could ultimately lead to a decreased risk of breast cancer. Preventive measures such as regular screening of mammograms and self- examination have been advocated as means to detect early cancer, which is generally curable. It is recommended that women should perform breast self-exams periodically to feel for any lumps or breast abnormalities. By age 40, 1 out of 235 women will have breast cancer. This statistic increases by age 60 to 1 out of 23 and by age 80, 1 out of every 10 women. Since age is the most important factor that influences cancer risk possibility, especially after 40 years, women should get mammograms, which can detect lumps that may otherwise be hard to feel. Furthermore, a healthy balanced diet and exercise are also important to help minimize cancer risks.
Scientists in Denmark have recently devised an almost 100% guaranteed tumor prevention strategy which involves prophylactic removal of the breast by mastectomy in persons at a high risk of developing breast cancer. It is debatable if this should be the recommended course for prevention of breast cancer in persons with history of familial high incidence of breast cancer. Although it is a drastic measure, these studies have shown that this procedure reduces cancer risk by at least 90%, and it may be a big step towards decreasing breast cancer rates in high-risk patients.
Disclaimer: Information presented in this article is not intended to diagnose, treat, cure or mitigate any disease. If you have a medical condition, please consult a health professional.
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